Ferrocenyl-based electron-rich phosphines and compounds thereof

Abstract

A ferrocenyl-based phosphine compound is provided that contains (i) a bis (adamantyl) phosphine group on a first cyclopentadiene ring and a pentaaryl substituent on a second cyclopentadiene ring, or (ii) a bis (adamantyl) phosphine group on the first cyclopentadiene ring and the second cyclopentadiene ring, respectively. Further provided is a scalable process for the synthesis of the ferrocenyl-based phosphine compound, starting from readily available starting materials with simple post-processing, as well as various pre-catalysts containing a transition metal and the ferrocenyl-based phosphine compound as ligands.

Description

Technical Field

[0001] This application claims priority to U.S. Provisional Patent Application No. 63 / 494077, filed April 4, 2023, the contents of which are hereby incorporated in their entirety.

[0002] Novel ferrocenyl-based electron-rich phosphine compounds are provided, which contain (i) a di(adamantyl)phosphine group on the first cyclopentadiene ring and a pentaaryl substituent on the second cyclopentadiene ring (AdQPhos type), or (ii) a di(adamantyl)phosphine group on the first cyclopentadiene ring and the second cyclopentadiene ring respectively (AdMPhos type).

[0003] A scalable method for synthesizing the novel ferrocene-based electron-rich phosphine compounds is also provided, which begins with readily available starting materials that have simple work-up.

[0004] Various precatalysts containing transition metals and the novel ferrocene-based electron-rich phosphine compounds as ligands are also provided. Such precatalysts include, for example, Ar-X or XX transition metal complexes of the type LMARaX (Formula VI) and LMX2 (Formula VII), R-allyl transition metal complexes of the type LM(R-allyl)X (Formula VIII) and LM(R-allyl) (Formula IX), and (c) LM(biphenyl-NR)X (Formula X) and LM(biphenyl-NR). + N-biphenyl transition metal complexes of type (Formula XI), such as Figure 1 As shown, these complexes are useful in catalysis.

[0005] All compounds and complexes prepared in this paper were comprehensively characterized by various analytical techniques, such as NMR, elemental analysis, and single-crystal X-ray diffraction. Compared with QPhos and other ligands known in the prior art, they exhibit superior performance in various types of cross-coupling reactions (e.g., (1)C(sp) 2 )-C(sp 2 (2) C(sp) coupling reaction 2 )-C(sp 3 Coupling reaction, (3)C(sp) 2 )-N coupling reaction, (4)C(sp 2 )-O coupling reaction, (5)C(sp 2 )-S coupling reaction, (6)C(sp 2 (7) α-arylation of amides, esters, nitriles, nitroalkanes, ketones, etc. exhibits superior catalytic activity.

[0006] Therefore, a method for carrying out a transition metal-catalyzed coupling reaction between a first substrate and a second substrate is further provided, wherein the transition metal-catalyzed coupling reaction is preferably selected from C(sp...) 2 )-C(sp 2 Coupling reaction, C(sp) 2 )-C(sp 3 Coupling reaction, C(sp) 2 )-N coupling reaction, C(sp 2 )-O coupling reaction, C(sp 2 )-S coupling reaction, C(sp 2 )-P coupling reaction or α-arylation of amides, esters, nitriles, nitroalkanes or ketones. Figure 2 Non-limiting examples of the mentioned reactions are shown. Background Technology

[0007] The rise of palladium as a 21st-century metal is attributed to its applications in catalysis. (1) Phosphine ligands play a crucial role in catalysis. These ligands define their overall potency and efficiency in catalysis through their electronic, spatial, and other kinetic / thermodynamic properties. Ferrocene-based bisphosphines constitute an important class of modern ligands, widely used in various cross-coupling reactions such as dtbpf, dppf, dippf, and MPhos. (2) Synthetic and applied studies related to ferrocene monophosphines have been limited by various challenges associated with their synthesis, purification, and scale-up. Sollot and colleagues reported the first monosubstituted ferrocene phosphine via Friedel-Craft's route in 1962 (with poor yield and selectivity); (3) Subsequently, Knox and Pauson, (4) Juge and Genet, (5) Jamison (6) This groundbreaking work outlines a general strategy for introducing dialkyl / arylphosphine motifs into ferrocene rings.

[0008] Despite these advances, the direct application of these ligands in cross-coupling reactions remained limited until the early 2000s. In 2002, Hartwig and colleagues reported the synthesis of pentaphenylferrocene phosphine (also known as QPhos) and their derivatives. (7) Compared to other non-arylated species, QPhos is relatively stable and exhibits unconventional catalytic activity for a variety of CC, CO, and CN cross-coupling reactions, although large-scale scalation of this ligand is challenging due to the involvement of chromatography. The scalability challenges of this excellent ligand, compared to the corresponding bisphosphine-ferrocene, limit its industrial applications.(8) Compared to other commercially available ligands, including QPhos, the precatalysts derived from these new ligands exhibit superior activity. (9) Despite these advances, there remains a need for new ligands that (1) address some of the existing challenges in cross-coupling and (2) have a synthesis suitable for manufacturing on a large scale, sufficient to prepare adequate quantities with purity acceptable for industrial applications.

[0009] In view of this, the present invention addresses two major advances in the field: (1) the development of a new class of electron-rich polyarylated ferrocene monophosphines and their transition metal complexes; and (2) the development / optimization of methods for their scalable synthesis for their use in commercial applications. These methods do not rely on any exhaustive purification techniques, such as chromatography.

[0010] In summary, this invention relates to the synthesis and catalytic applications of a new class of air-stable polyarylated ferrocene monophosphines and their transition metal complexes, as well as green routes for their scalable synthesis. Summary of the Invention

[0011] Novel ferrocene-based electron-rich phosphine compounds are provided, which contain (i) a di(adamantyl)phosphine group on the first cyclopentadiene ring and a pentaaryl substituent on the second cyclopentadiene ring (AdQPhos type), or (ii) a di(adamantyl)phosphine group on the first cyclopentadiene ring and the second cyclopentadiene ring respectively (AdMPhos type).

[0012] Therefore, in the first embodiment of the present invention, a compound of formula I is provided: in: CP 1 Represented by Equation II or Equation III R 1 Each occurrence is independently selected from arbitrarily substituted C6-C. 10 Aryl or C3-C9 heteroaryl; Ad is adamantyl alkyl, preferably 1-damantyl alkyl; and When present, each optional substituent is selected from C1-C4 alkyl, C1-C4 haloalkyl and C1-C4 alkoxy, preferably methyl, trifluoromethyl and methoxy.

[0013] In a second embodiment of the invention, a method for synthesizing a compound according to formula IV is provided, wherein the method comprises the following steps: (a) Lithate the compound according to formula A and react it with Ad2PY 2 The reaction is carried out to yield a compound according to formula B; and (b) The compound according to formula B is combined with R 1 Y 3 The reaction is carried out in the presence of a base and a catalytic amount of Pd(OAc)2 to give the compound according to formula IV; in: Y 1 Selected from halogen atoms or hydrogen atoms; Y 2 Y 3 They are selected independently from halogen atoms; R 1 Each occurrence is independently selected from arbitrarily substituted C6-C. 10 Aryl or C3-C9 heteroaryl; Ad is adamantyl alkyl, preferably 1-damantyl alkyl; and When present, each optional substituent is selected from C1-C4 alkyl, C1-C4 haloalkyl and C1-C4 alkoxy, preferably methyl, trifluoromethyl and methoxy.

[0014] In a third embodiment of the invention, a method for synthesizing a compound according to formula V is provided, wherein the method comprises the following steps: (a') Lithate the compound according to formula C and react it with Ad2PY 2 The reaction is carried out to obtain the compound according to formula V: in: Y 1 Selected from halogen atoms or hydrogen atoms; Y 2 They are selected independently from halogen atoms; and Ad is adamantyl, preferably 1-damantyl.

[0015] In a fourth embodiment of the invention, a precatalyst of formula VI or VII is provided: in: R 1 Each occurrence is independently selected from arbitrarily substituted C6-C. 10 Aryl or C3-C9 heteroaryl; Ad is adamantyl alkyl, preferably 1-damantyl alkyl; M is a transition metal selected from Group 9, Group 10 or Group 11; X is selected from halogens, trifluoromethanesulfonate (TfO) – ), tetrafluoroborate (BF4) – ), hexafluorophosphate (PF6) – ), mesylate (MsO) – ), Toluenesulfonate (TsO) – ), tetrakis[3,5-bis(trifluoromethyl)phenyl]borate (B[(CF3)2C6H3]4 – ), hexafluoroantimonate (SbF6) – ) and their combinations; Ar represents the substituted C6-C. 10 Aryl; and When present, each optional substituent is selected from C1-C4 alkyl, C1-C4 haloalkyl and C1-C4 alkoxy, preferably methyl, trifluoromethyl and methoxy.

[0016] In a fifth embodiment of the invention, a precatalyst of formula VIII or formula IX is provided: in: R 1 Each occurrence is independently selected from arbitrarily substituted C6-C. 10 Aryl or C3-C9 heteroaryl; Ad is adamantyl alkyl, preferably 1-damantyl alkyl; M is a transition metal selected from Group 9, Group 10 or Group 11; X is selected from halogens, trifluoromethanesulfonate (TfO) – ), tetrafluoroborate (BF4) – ), hexafluorophosphate (PF6) – ), mesylate (MsO) – ), Toluenesulfonate (TsO) – ), tetrakis[3,5-bis(trifluoromethyl)phenyl]borate (B[(CF3)2C6H3]4 – ), hexafluoroantimonate (SbF6) – ) and their combinations; R 2 Selected from H, C1-C4 alkyl and C6-C 10 Aryl group, preferably selected from H, Me, and Ph; and When present, each optional substituent is selected from C1-C4 alkyl, C1-C4 haloalkyl and C1-C4 alkoxy, preferably methyl, trifluoromethyl and methoxy.

[0017] In a sixth embodiment of the invention, a precatalyst of formula X or formula XI is provided: in: R 1 Each occurrence is independently selected from arbitrarily substituted C6-C. 10 Aryl or C3-C9 heteroaryl; Ad is adamantyl alkyl, preferably 1-damantyl alkyl; M is a transition metal selected from Group 9, Group 10 or Group 11; X is selected from halogens, trifluoromethanesulfonate (TfO) – ), tetrafluoroborate (BF4) – ), hexafluorophosphate (PF6) – ), mesylate (MsO) – ), Toluenesulfonate (TsO) – ), tetrakis[3,5-bis(trifluoromethyl)phenyl]borate (B[(CF3)2C6H3]4 – ), hexafluoroantimonate (SbF6) – ) and their combinations; R 3 Selected from H, Me, NHMe, Ph, and NHPh; and When present, each optional substituent is selected from C1-C4 alkyl, C1-C4 haloalkyl and C1-C4 alkoxy, preferably methyl, trifluoromethyl and methoxy.

[0018] In a seventh embodiment of the present invention, a method for carrying out a transition metal-catalyzed coupling reaction between a first substrate and a second substrate is provided, wherein the method includes the following steps: (a) Providing in a reaction vessel (i) a compound and a transition metal source according to a first embodiment of the invention, or (ii) a precatalyst according to any one of a fourth, fifth, or sixth embodiment of the invention; (b) Add the first and second substrates to the reaction vessel; and (c) React the first and second substrates at a temperature and time sufficient for transition metal catalytic coupling reactions. Attached Figure Description

[0019] Figure 1 Various precatalysts are shown: (a) Ar-X or XX transition metal complexes of the type LMARaX (Formula VI) and LMX2 (Formula VII), (b) R-allyl transition metal complexes of the type LM(R-allyl)X (Formula VIII) and LM(R-allyl) (Formula IX), and (c) LM(biphenyl-NR)X (Formula X) and LM(biphenyl-NR). + N-biphenyl transition metal complexes of type (Formula XI).

[0020] Figure 2Examples of transition metal-catalyzed coupling reactions are shown below: a) C(sp 2 )-C(sp 2 Coupling reaction, b) C(sp) 2 )-C(sp 3 Coupling reaction, c)C(sp) 2 )-N coupling reaction, d)C(sp 2 )-O coupling reaction, e)C(sp 2 f) α-arylation of ketones, g) α-arylation of nitriles, h) α-arylation of esters, i) α-arylation of nitroalkanes, j) α-arylation of amides, and k) C(sp) coupling reactions. 2 )-P coupling reaction, wherein when R is attached to a heteroatom (e.g., N, P, etc.), R represents hydrogen or a substituent, and wherein when R is attached to an aromatic ring system, R represents hydrogen or one or more substituents. Detailed Implementation

[0021] The novel compounds and precatalysts described in this article (e.g.) Figure 1 Those shown overcome the problems of traditional catalysts and provide a powerful new route for previously challenging cross-coupling reactions, while being scalable so that they can be obtained and provided in sufficient quantities and purity for industrial applications.

[0022] These new compounds and precatalysts are based on a ferrocene-based framework and contain (i) a bis(adamantyl)phosphine group on the first cyclopentadiene ring and a pentaaryl substituent on the second cyclopentadiene ring, or (ii) a bis(adamantyl)phosphine group on the first and second cyclopentadiene rings, respectively. As described herein, they offer significant advantages over existing ligands and precatalysts.

[0023] Traditional methods for synthesizing ferrocene-based phosphine compounds are not suitable for incorporating two Ad2P moieties into ferrocene-based compounds to prepare Fc(Ad2P)(Ad2P) type compounds.

[0024] This article describes novel ferrocene-based electron-rich phosphine compounds containing (i) a di(adamantyl)phosphine group on a first cyclopentadiene ring and a pentaaryl substituent on a second cyclopentadiene ring (AdQPhos type), or (ii) a di(adamantyl)phosphine group on a first cyclopentadiene ring and a second cyclopentadiene ring (AdMPhos type).

[0025] The invention also provides a scalable synthesis of the novel ferrocene-based electron-rich phosphine compound, which begins with readily available starting materials with simple post-processing.

[0026] It also provides, for example Figure 1The precatalyst shown, containing a transition metal and the novel ferrocene-based electron-rich phosphine compound as a ligand, is useful in catalysis.

[0027] A method for a transition metal-catalyzed coupling reaction between a first substrate and a second substrate is also provided, wherein the transition metal-catalyzed coupling reaction is preferably selected from C(sp...) 2 )-C(sp 2 Coupling reaction, C(sp) 2 )-C(sp 3 Coupling reaction, C(sp) 2 )-N coupling reaction, C(sp 2 )-O coupling reaction, C(sp 2 )-S coupling reaction, C(sp 2 α-P coupling reactions or α-arylation of amides, esters, nitriles, nitroalkanes, or ketones. See also, for non-limiting examples of the reactions mentioned. Figure 2 .

[0028] In a first embodiment of the invention, a compound of formula I is provided: in: CP 1 Represented by Equation II or Equation III R 1 Each occurrence is independently selected from arbitrarily substituted C6-C. 10 Aryl or C3-C9 heteroaryl; Ad is adamantyl alkyl, preferably 1-damantyl alkyl; and When present, each optional substituent is selected from C1-C4 alkyl, C1-C4 haloalkyl and C1-C4 alkoxy, preferably methyl, trifluoromethyl and methoxy.

[0029] In a preferred embodiment of the invention, the compound of formula I is represented by formula IV: in: R 1 Each occurrence is independently selected from arbitrarily substituted C6-C. 10 Aryl or C3-C9 heteroaryl; and Ad is adamantyl, preferably 1-damantyl.

[0030] Preferably, in Formula II and / or Formula IV of the present invention, R 1Each of the optional substituents is independently selected from the substituted C6 aryl groups each time it appears; and each optional substituent (when present) is selected from C1-C4 alkyl, C1-C4 haloalkyl, and C1-C4 alkoxy groups, preferably methyl, trifluoromethyl, and methoxy. More preferably, in formula II and / or formula IV of the invention, R 1 Each time it appears, it is independently selected from phenyl, tolyl, and (trifluoromethyl)phenyl. Most preferably, in formula II and / or formula IV of the present invention, R 1 Each time it appears, it is independently selected from phenyl, p-tolyl, and p-(trifluoromethyl)phenyl.

[0031] In a preferred embodiment of the invention, the compound of formula I is represented by formula V: Wherein Ad is adamantyl, preferably 1-damantyl.

[0032] In a more preferred embodiment of the invention, the compound of formula I is selected from: .

[0033] In a second embodiment of the invention, a method for synthesizing a compound according to formula IV is provided, wherein the method comprises the following steps: (a) Lithate the compound according to formula A and react it with Ad2PY 2 The reaction is carried out to yield a compound according to formula B; and (b) The compound according to formula B is combined with R 1 Y 3 The reaction is carried out in the presence of a base and a catalytic amount of Pd(OAc)2 to give the compound according to formula IV; in: Y 1 Selected from halogen atoms or hydrogen atoms; Y 2 Y 3 They are selected independently from halogen atoms; R 1 Each occurrence is independently selected from arbitrarily substituted C6-C. 10 Aryl or C3-C9 heteroaryl; Ad is adamantyl alkyl, preferably 1-damantyl alkyl; and When present, each optional substituent is selected from C1-C4 alkyl, C1-C4 haloalkyl and C1-C4 alkoxy, preferably methyl, trifluoromethyl and methoxy.

[0034] Preferably, Y1 Selected from Cl, Br, I, and H; and Y 2 Y 3 They are independently selected from Cl, Br, and I. More preferably, Y 1 For Br or H; Y 2 For Cl; and Y 3 It is Cl.

[0035] In the second implementation scheme R 1 The preferred, more preferred, and most preferred embodiments are the same as those given above for the first embodiment.

[0036] Preferably, the lithiation in step (a) is carried out by reacting the compound according to formula A with an organolithium reagent. More preferably, the lithiation in step (a) is carried out by reacting the compound according to formula A with an organolithium reagent selected from nBuLi, sBuLi, and tBuLi. Most preferably, the lithiation in step (a) is carried out by reacting the compound according to formula A with nBuLi.

[0037] Preferably, step (a) is carried out in an ether solvent. More preferably, step (a) is carried out in tetrahydrofuran.

[0038] Preferably, the lithiation in step (a) is performed at a temperature of about -78°C. More preferably, the lithiation in step (a) is performed at a temperature of about -78°C, and the reaction with Ad2PY in step (a) is... 2 The reaction was carried out over a temperature gradient of approximately -78°C to room temperature.

[0039] Preferably, the base in step (b) is an alkali metal alkoxide or an alkaline earth metal alkoxide. More preferably, the base in step (b) is a sodium alkoxide. Most preferably, the base in step (b) is NaOtBu.

[0040] Preferably, step (b) is performed at a temperature ranging from about 80°C to about 130°C. More preferably, step (b) is performed at a temperature ranging from about 100°C to about 120°C. Most preferably, step (b) is performed at a temperature of about 110°C.

[0041] In a third embodiment of the invention, a method for synthesizing a compound according to formula V is provided, wherein the method comprises the following steps: (a') Lithate the compound according to formula C and react it with Ad2PY 2 The reaction is carried out to obtain the compound according to formula V: in: Y 1 Selected from halogen atoms or hydrogen atoms; Y2 Selected from halogen atoms; and Ad is adamantyl, preferably 1-damantyl.

[0042] Preferably, Y 1 Selected from Cl, Br, I, and H; and Y 2 Selected from Cl, Br, and I. More preferably, Y 1 It is Br or H; and Y 2 It is Cl.

[0043] Preferably, the lithiation in step (a') is carried out by reacting the compound according to formula C with an organolithium reagent. More preferably, the lithiation in step (a') is carried out by reacting the compound according to formula C with an organolithium reagent selected from nBuLi, sBuLi, and tBuLi. Most preferably, the lithiation in step (a') is carried out by reacting the compound according to formula C with nBuLi.

[0044] Preferably, step (a') is carried out in an ether solvent. More preferably, step (a') is carried out in tetrahydrofuran.

[0045] Preferably, the lithiation in step (a') is performed at a temperature of about -78°C. More preferably, the lithiation in step (a') is performed at a temperature of about -78°C, and the reaction with Ad2PY in step (a') is... 2 The reaction was carried out over a temperature gradient from approximately -78°C to room temperature.

[0046] In a fourth embodiment of the invention, a precatalyst of formula VI or VII is provided: in: R 1 Each occurrence is independently selected from arbitrarily substituted C6-C. 10 Aryl or C3-C9 heteroaryl; Ad is adamantyl alkyl, preferably 1-damantyl alkyl; M is a transition metal selected from Group 9, Group 10 or Group 11; X is selected from halogens, trifluoromethanesulfonate (TfO) – ), tetrafluoroborate (BF4) – ), hexafluorophosphate (PF6) – ), mesylate (MsO) – ), Toluenesulfonate (TsO) – ), tetrakis[3,5-bis(trifluoromethyl)phenyl]borate (B[(CF3)2C6H3]4 – ), hexafluoroantimonate (SbF6) – ) and their combinations; Ar represents the substituted C6-C. 10 Aryl; and When present, each optional substituent is selected from C1-C4 alkyl, C1-C4 haloalkyl and C1-C4 alkoxy, preferably methyl, trifluoromethyl and methoxy.

[0047] Preferably, in Formula VI of the present invention, R 1 Each of the optional substituents is independently selected from the substituted C6 aryl groups each time it appears; and each optional substituent (when present) is selected from C1-C4 alkyl, C1-C4 haloalkyl, and C1-C4 alkoxy groups, preferably methyl, trifluoromethyl, and methoxy. More preferably, in formula VI of the invention, R 1 Each time it appears, it is independently selected from phenyl, tolyl, and (trifluoromethyl)phenyl. Most preferably, in formula VI of the invention, R 1 Each time it appears, it is independently selected from phenyl, p-tolyl, and p-(trifluoromethyl)phenyl.

[0048] Preferably, in formula VI and / or formula VII of the present invention, M is selected from Co, Rh, Ir, Ni, Pd, Pt, Cu, Ag, and Au. More preferably, in formula VI and / or formula VII of the present invention, M is selected from Ni, Pd, and Pt. Most preferably, in formula VI and / or formula VII of the present invention, M is Pd.

[0049] Preferably, in formula VI and / or formula VII of the present invention, X is selected from chloride ions (Cl... – ), bromide ions (Br) – ), iodide ions (I) – ), trifluoromethanesulfonate (TfO) – ), mesylate (MsO) – ), Toluenesulfonate (TsO) – ) and its combinations.

[0050] Preferably, in Formula VI of the present invention, Ar is an optionally substituted C6 aryl group. More preferably, in Formula VI of the present invention, Ar is selected from Ph, tolyl, and (trifluoromethyl)phenyl. Most preferably, in Formula VI of the present invention, Ar is selected from p-tolyl and p-(trifluoromethyl)phenyl.

[0051] In a preferred embodiment of the present invention, the precatalyst of formula VI or formula VII is selected from: in: Ad is 1-adamantyl; Ar is Ph or p-(trifluoromethyl)phenyl; and X is selected from chloride ions (Cl... – ), bromide ions (Br)– ), trifluoromethanesulfonate (TfO) – ) and mesylate (MsO) – ).

[0052] In a fifth embodiment of the invention, a precatalyst of formula VIII or formula IX is provided: in: R 1 Each occurrence is independently selected from arbitrarily substituted C6-C. 10 Aryl or C3-C9 heteroaryl; Ad is adamantyl alkyl, preferably 1-damantyl alkyl; M is a transition metal selected from Group 9, Group 10 or Group 11; X is selected from halogens, trifluoromethanesulfonate (TfO) – ), tetrafluoroborate (BF4) – ), hexafluorophosphate (PF6) – ), mesylate (MsO) – ), Toluenesulfonate (TsO) – ), tetrakis[3,5-bis(trifluoromethyl)phenyl]borate (B[(CF3)2C6H3]4 – ), hexafluoroantimonate (SbF6) – ) and their combinations; R 2 Selected from H, C1-C4 alkyl and C6-C 10 Aryl group, preferably selected from H, Me, and Ph; and When present, each optional substituent is selected from C1-C4 alkyl, C1-C4 haloalkyl and C1-C4 alkoxy, preferably methyl, trifluoromethyl and methoxy.

[0053] Preferably, in formula VIII of the present invention, R 1 Each of the optional substituents is independently selected from the substituted C6 aryl groups each time it appears; and each optional substituent (when present) is selected from C1-C4 alkyl, C1-C4 haloalkyl, and C1-C4 alkoxy groups, preferably methyl, trifluoromethyl, and methoxy. More preferably, in formula VIII of the invention, R 1 Each time it appears, it is independently selected from phenyl, tolyl, and (trifluoromethyl)phenyl. Most preferably, in formula VIII of the invention, R 1 Each time it appears, it is independently selected from phenyl, p-tolyl, and p-(trifluoromethyl)phenyl.

[0054] Preferably, in formula VIII and / or formula IX of the present invention, M is selected from Co, Rh, Ir, Ni, Pd, Pt, Cu, Ag, and Au. More preferably, in formula VIII and / or formula IX of the present invention, M is selected from Ni, Pd, and Pt. Most preferably, in formula VIII and / or formula IX of the present invention, M is Pd.

[0055] Preferably, in formula VIII and / or formula IX of the present invention, X is selected from chloride ions (Cl... – ), bromide ions (Br) – ), iodide ions (I) – ), trifluoromethanesulfonate (TfO) – ), tetrafluoroborate (BF4) – ), hexafluorophosphate (PF6) – ), mesylate (MsO) – ), Toluenesulfonate (TsO) – ) and its combinations.

[0056] Preferably, in formula VIII and / or formula IX of the present invention, R 2 Selected from H, Me, and Ph.

[0057] In a preferred embodiment of the present invention, the precatalyst of formula VIII or formula IX is selected from: in: Ad is 1-adamantyl; R 2 Selected from H, Me, and Ph; and X is selected from chloride ions (Cl... – ), bromide ions (Br) – ), iodide ions (I) – ), trifluoromethanesulfonate (TfO) – ), tetrafluoroborate (BF4) – ) and hexafluorophosphate (PF6) – ).

[0058] In a sixth embodiment of the invention, a precatalyst of formula X or formula XI is provided: in: R 1 Each occurrence is independently selected from arbitrarily substituted C6-C. 10 Aryl or C3-C9 heteroaryl; Ad is adamantyl alkyl, preferably 1-damantyl alkyl; M is a transition metal selected from Group 9, Group 10 or Group 11; X is selected from halogens, trifluoromethanesulfonate (TfO)– ), tetrafluoroborate (BF4) – ), hexafluorophosphate (PF6) – ), mesylate (MsO) – ), Toluenesulfonate (TsO) – ), tetrakis[3,5-bis(trifluoromethyl)phenyl]borate (B[(CF3)2C6H3]4 – ), hexafluoroantimonate (SbF6) – ) and their combinations; R 3 Selected from H, Me, NHMe, Ph, and NHPh; and When present, each optional substituent is selected from C1-C4 alkyl, C1-C4 haloalkyl and C1-C4 alkoxy, preferably methyl, trifluoromethyl and methoxy.

[0059] Preferably, in formula X of the present invention, R 1 Each of the optional substituents is independently selected from the substituted C6 aryl groups each time it appears; and each optional substituent (when present) is selected from C1-C4 alkyl, C1-C4 haloalkyl, and C1-C4 alkoxy groups, preferably methyl, trifluoromethyl, and methoxy. More preferably, in formula X of the invention, R 1 Each time it appears, it is independently selected from phenyl, tolyl, and (trifluoromethyl)phenyl. Most preferably, in formula X of the invention, R 1 Each time it appears, it is independently selected from phenyl, p-tolyl, and p-(trifluoromethyl)phenyl.

[0060] Preferably, in formula X and / or formula XI of the present invention, M is selected from Co, Rh, Ir, Ni, Pd, Pt, Cu, Ag, and Au. More preferably, in formula X and / or formula XI of the present invention, M is selected from Ni, Pd, and Pt. Most preferably, in formula X and / or formula XI of the present invention, M is Pd.

[0061] Preferably, in formula X and / or formula XI of the present invention, X is selected from chloride ions (Cl... – ), bromide ions (Br) – ), iodide ions (I) – ), trifluoromethanesulfonate (TfO) – ), tetrafluoroborate (BF4) – ), hexafluorophosphate (PF6) – ), mesylate (MsO) – ), Toluenesulfonate (TsO) – ) and its combinations.

[0062] Preferably, in formula X and / or formula XI of the present invention, R 3 Selected from H, Me, and NHMe.

[0063] In a preferred embodiment of the present invention, the precatalyst of formula X or formula XI is selected from: in: Ad is 1-adamantyl; and X is the mesylate ion (MsO) – ).

[0064] In a seventh embodiment of the present invention, a method for carrying out a transition metal-catalyzed coupling reaction between a first substrate and a second substrate is provided, wherein the method includes the following steps: (a) Providing (i) a compound and a transition metal source according to the first embodiment of the invention, or (ii) a pre-catalyst according to any one of the fourth, fifth or sixth embodiments of the invention in the reaction vessel; (b) Adding the first and second substrates to the reaction vessel; and (c) React the first and second substrates at a temperature and time sufficient for transition metal catalytic coupling reactions.

[0065] In a preferred embodiment of the present invention, the transition metal source in the seventh embodiment is a Pd metal source, and the precatalyst is a Pd precatalyst.

[0066] In a more preferred embodiment of the present invention, the transition metal source in the seventh embodiment is selected from Pd(cod)X. 2、 [Pd(allyl)X]2, [Pd(crotonyl)X]2, [Pd(cinnamyl)X]2, [(2-biphenyl-NHR)Pd(OMs)]2, (cod)Pd(CH2CMe2C6H4), (cod)Pd(CH2TMS)2, Pd(dba)2, Pd2(dba)3 and PdX2(CH3CN)2; wherein cod = 1,5-cyclooctadiene; X = Cl or Br; R = H, Me or Ph; Ms = methanesulfonyl; TMS = trimethylsilyl; and dba = dibenzylideneacetone.

[0067] In the most preferred embodiment of the present invention, the transition metal source in the seventh embodiment is selected from Pd(cod)Cl2, [Pd(allyl)Cl]2, [Pd(crotonyl)Cl]2, [Pd(cinnamyl)Cl]2, [(2-biphenyl-NHR)Pd(OMs)]2, (cod)Pd(CH2CMe2C6H4), (cod)Pd(CH2TMS)2, Pd(dba)2, Pd2(dba)3, and PdCl2(CH3CN)2; wherein cod = 1,5-cyclooctadiene; R = H, Me, or Ph; Ms = methanesulfonyl; TMS = trimethylsilyl; and dba = dibenzylideneacetone.

[0068] In a preferred embodiment of the present invention, the transition metal catalytic coupling reaction in the seventh embodiment is selected from C(sp...) 2 )-C(sp 2 Coupling reaction, C(sp) 2 )-C(sp 3 Coupling reaction, C(sp) 2 )-N coupling reaction, C(sp 2 )-O coupling reaction, C(sp 2 )-S coupling reaction, C(sp 2 )-P coupling reaction or α-arylation of amides, esters, nitriles, nitroalkanes or ketones.

[0069] Preferably, in step (c) of the method for carrying out transition metal catalytic coupling reaction according to the present invention, the temperature is from room temperature to 130°C, more preferably from room temperature to 100°C, and most preferably from room temperature to 70°C.

[0070] In a preferred embodiment of the invention, the compound provided in step (a) of the method for carrying out a transition metal catalytic coupling reaction according to the invention is selected from: .

[0071] In a preferred embodiment of the invention, the precatalyst provided in step (a) of the method for carrying out a transition metal catalytic coupling reaction according to the invention is selected from: .

[0072] In a preferred embodiment of the invention, the first substrate provided in step (b) of the method for carrying out a transition metal-catalyzed coupling reaction according to the invention is selected from aromatic compounds, which are substituted with halogens, preferably Br or Cl, and optionally contain one or more substituents selected from alkyl, alkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, halogen, hydroxyl, nitro and nitrile.

[0073] In a more preferred embodiment of the invention, the first substrate provided in step (b) of the method for carrying out a transition metal catalytic coupling reaction according to the invention is selected from C6-C. 18 Aromatic compounds, which are substituted with halogens, preferably Br or Cl, and optionally contain compounds selected from C1-C2. 10 Alkyl, C1-C 10 Alkoxy, C6-C 10 Aryl, C6-C 10 One or more substituents of aryloxy, C3-C9 heteroaryl, C3-C9 heteroaryloxy, F, Br, Cl, I, hydroxyl, nitro and nitrile.

[0074] In the most preferred embodiment of the invention, the first substrate provided in step (b) of the method for carrying out a transition metal-catalyzed coupling reaction according to the invention is selected from C6 aromatic compounds, which are substituted with Br or Cl, and optionally contain one or more substituents selected from C1-C5 alkyl, C1-C5 alkoxy, C6 aryl, C6 aryloxy, F, Br, Cl, I, hydroxyl, nitro and nitrile.

[0075] In a preferred embodiment of the invention, the second substrate provided in step (b) of the method for carrying out transition metal catalytic coupling reaction according to the invention is selected from alkyl metal halides, alkoxides, boric acids, thiols, ketones, amides, nitroalkanes, nitriles, esters, and phosphines.

[0076] In a more preferred embodiment of the invention, the second substrate provided in step (b) of the method for carrying out a transition metal-catalyzed coupling reaction according to the invention is selected from alkyl magnesium halides containing 1 to 20 carbon atoms, alkyl zinc halides containing 1 to 20 carbon atoms, alkoxides containing 1 to 20 carbon atoms, boric acids containing 1 to 20 carbon atoms, alkyl thiols containing 1 to 20 carbon atoms, ketones containing 2 to 20 carbon atoms, amides containing 2 to 20 carbon atoms, nitroalkanes containing 1 to 20 carbon atoms, nitriles containing 1 to 20 carbon atoms, esters containing 2 to 20 carbon atoms, and phosphines containing 1 to 20 carbon atoms, optionally substituted with one or more substituents selected from fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, phenyl, methoxy, ethoxy, propoxy, and phenoxy.

[0077] definition The precatalyst complexes described herein have at least one metallic center containing a transition metal (“M”). Examples of transition metals include, but are not limited to, those in Groups 9, 10, and 11 of the periodic table. Group 9 metals include Co, Rh, and Ir. Group 10 elements include Ni, Pd, and Pt. Group 11 elements include Cu, Ag, and Au.

[0078] As used herein, the terms “about” or “approximately”, when used in conjunction with a measurable numerical variable, refer to the indicated value of the variable and all variable values ​​within the experimental error of the indicated value (e.g., within the 95% confidence limit of the mean) or within ±10% (preferably ±5%) of the indicated value (whichever is greater).

[0079] As used herein, the term "Ad" refers to the adamantyl group, i.e., the group of the formula (-C 10 H 15 ) tricyclic bridged hydrocarbons. 1-adamantyl can be written as (-C(CH)3(CH2)6), and 2-adamantyl can be written as (-CH(CH)4(CH2)5).

[0080] As used in this article, the term "tBu" refers to the tert-butyl group, which is a branched alkyl group of the formula (-C4H9), which can also be written as (-C(CH3)3).

[0081] As used in this article, the term "iPr" refers to the isopropyl group, which is a branched alkyl group of the formula (-C3H7), which can also be written as (-CH(CH3)2).

[0082] As used herein, the term "alkyl" refers to a saturated hydrocarbon chain, such as, but not limited to, methyl, ethyl, propyl, and butyl. Alkyl groups can be straight-chain or branched. For example, as used herein, propyl includes n-propyl and isopropyl; butyl includes n-butyl, sec-butyl, isobutyl, and tert-butyl, etc.

[0083] As used herein, the term "cycloalkyl" refers to a cyclic group of a saturated hydrocarbon, such as, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl (Cy). It also includes bridged cyclic groups of saturated hydrocarbons, such as, but not limited to, adamantyl.

[0084] As used herein, the term "aryl" refers to an aromatic hydrocarbon group. Aryl groups include, for example, phenyl, biphenyl, naphthyl, anthracene, and so on, as well as their substituted forms.

[0085] As used herein, the term "heteroaryl" refers to an aromatic group containing one or more heteroatoms. Preferably, the heteroatoms are selected from O, N, and / or S. Heteroaryl groups include, for example, furanyl, thiopheneyl, pyrroloyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, pyridinyl, pyridazinyl, 1,3,5-triazinyl, indolyl, benzofuranyl, benzoxazolyl, isoquinolinyl, quinolinyl, quinazolinyl, quinoxalinyl, benzoxazinyl, purineyl, pteridinyl, etc., and their respective substituted forms.

[0086] As used herein, “substituted” means that one or more hydrogen atoms of the described compound or functional group are replaced by another functional group or substituent. For example, a substituted phenyl group may include one or more substituents replacing any hydrogen atom on the benzene ring. In some embodiments, there may be one substituent at the ortho, meta, or para positions. In other embodiments, there may be substituents at two ortho positions or two meta positions. In still other embodiments, an optionally substituted phenyl group may include, for example, substituents at the ortho and para positions, or meta and para positions. In some embodiments having multiple substituents, all substituents are identical; in other embodiments having multiple substituents, the substituents are different from each other. Typical substituents include, but are not limited to, C1-C4 alkyl, C1-C4 haloalkyl, and C1-C4 alkoxy groups. When a functional group is described as “optionally substituted,” the functional group may have one or more substituents, or no substituents. Example

[0087] Synthesis of Phosphine Compounds and Related Palladium Precatalysts Example 1. Synthesis of AdQPhos (1) and its derivatives (2) and (3) Step 1: Synthesis of di-1-adamantylphosphine ferrocene (1b) 1-Bromoferrocene (1a, 4.0 g, 15.1 mmol) was placed in a 50 mL Schlenk flask with a PTFE-coated stir bar. The container was sealed with a rubber diaphragm, evacuated, and purged with nitrogen. This cycle was repeated twice. Next, anhydrous THF (40 mL) was added, and the mixture was stirred for 5 minutes. The solution was cooled to -78°C, and then nBuLi (2.6 M, 5.7 mL, 15.1 mmol in hexane) was added in another flask over 15 minutes. The mixture was stirred for 1 hour, and a clear precipitation (indicating lithiation) was observed. Subsequently, di(1-adamantyl)chlorophosphine (0.75 M, 15.1 mmol) in THF was added dropwise. The solution was allowed to warm to room temperature and stirred overnight (18 hours). After 18 hours, a large amount of precipitation was observed, and the reaction mixture was sampled. 31 P NMR analysis indicated complete consumption of the starting material. The solution was cooled to 0–5°C in an ice bath. The pure product precipitated out and was filtered under nitrogen. The resulting solid was washed with diethyl ether and pentane to give pure product 1b (yellow solid, 5.6 g, 76.6%).

[0088] Step 2: Synthesis of AdQPhos (1) 1b (0.972 g, 2 mmol), sodium tert-butoxide (1.9 g, 20 mmol), and palladium acetate (22.4 mg, 0.1 mmol) were placed in a 50 mL three-necked round-bottom flask with a PTFE-coated stir bar. The container was evacuated and purged with nitrogen. This cycle was repeated twice. Subsequently, chlorobenzene (20 mL, 197.2 mmol) was added to dissolve the reactants. The mixture was stirred at room temperature for 15 minutes. Further, the mixture was refluxed at 110–120°C for 18 hours. Reaction samples were taken for analysis. 31 P NMR indicated complete consumption of 1b. The mixture was then cooled to room temperature, diluted with DCM (20 mL), and filtered through a celite plug. The celite plug was washed with DCM to elute any remaining product. The solvent was removed under reduced pressure. The resulting deep red solid was washed with acetone to yield final product 1 (1.2 g, 71%). 1 H NMR (500 MHz, CD2Cl2) δ 7.33 – 7.31 (m, 10H), 7.14 – 7.07(m, 15H), 4.68 (d, J = 5 Hz, 2H), 4.47 (d, J = 5 Hz, 2H), 1.92 – 1.89 (m, 6H), 1.58 – 1.57 (m, 6H), 1.58 – 1.57 (m, 12H), 1.50 – 1.47 (m, 6H); 31 P NMR (202MHz) 18.4 ppm.

[0089] Similarly, the synthesized products (p-tolyl)AdQPhos(2) and ( p -CF3-C6H4)AdQPhos(3), except that chlorobenzene is replaced with a suitable chloroaromatic hydrocarbon.

[0090] (p-Tolyl)AdQPhos(2): 1 H NMR (500 MHz, CD2Cl2) δ 7.15 (d, J = 10 Hz, 10H), 6.87 (d, J = 10 Hz, 10H), 4.56 (d, J = 5 Hz, 2H), 4.34 (d, J= 5 Hz, 2H), 2.25 (s, 15H), 1.86 – 1.84 (m, 6H), 1.64 – 1.61 (m, 6H), 1.54 – 1.53 (m, 12H), 1.44 – 1.42 (m, 6H); 31 P NMR (202 MHz) 18.9 ppm.

[0091] ( p -CF3-C6H4)AdQPhos(3): 1 H NMR (500 MHz, CD2Cl2) δ 7.43 –7.39 (m, 20H),4.69 (d, J = 5 Hz, 2H), 4.49 (d, J = 5 Hz, 2H), 4.88 (s, 4H), 1.85 – 1.82 (m, 6H), 1.64 – 1.52 (m, 18H), 1.44 – 1.41 (m, 6H); 31 P NMR (202 MHz) 16.5 ppm.

[0092] Example 2. Synthesis of palladium precatalyst (Pd-1.2) (allyl / crotonyl / cinnamonyl type) AdQPhos (1,346.4 mg, 0.4 mmol) and the palladium precursor (80 mg, 0.2 mmol) were placed in a 20 mL Schlenk flask with a PTFE-coated stir bar. The flask was sealed with a rubber diaphragm, evacuated, and purged with nitrogen. This cycle was repeated twice. Next, anhydrous THF (5 mL) was added, and the mixture was stirred for 2 hours. Subsequently, a sample of the reaction was taken. 31 P NMR analysis indicated complete consumption of ligand 1. The solvent was removed, and the resulting solid was washed with pentane to yield the final product Pd-1.2 (412 mg, 96%).

[0093] (AdQPhos)Pd(crotonyl)Cl(Pd-1.2): 1H NMR (500 MHz, CD2Cl2) δ 7.26 – 7.23(m, 9H), 7.19 – 7.12 (m, 6H), 7.10 – 7.03 (m, 10H), 5.14 (bs, 1H), 4.81 –4.73 (m, 2H), 4.63 (bs, 2H), 4.2 – 4.15 (m, 1H), 3.70 – 3.67 (m, 1H), 2.20 –2.04 (m, 10 H), 1.86 – 1.77 (m, 9H), 1.62 – 1.52 (m, 15H); 31 P NMR (202 MHz) 61.0 ppm.

[0094] Example 3. Synthesis of palladium precatalyst (Pd-1.4) (palladium ring G3 type) AdQphos (1,346.4 mg, 0.4 mmol) and the palladium precursor (148 mg, 0.2 mmol) were placed in a 20 mL Schlenk flask with a PTFE-coated stir bar. The flask was sealed with a rubber diaphragm, evacuated, and purged with nitrogen. This cycle was repeated twice. Next, anhydrous DCM (5 mL) was added, and the mixture was stirred for 2 hours. Subsequently, a sample of the reaction was taken. 31 P NMR analysis showed complete consumption of ligand 1. The solvent was removed and the resulting solid was washed with pentane to yield the final product Pd-1.4 (349 mg, 94%).

[0095] (AdQPhos) Pd G3 (Pd-1.4): 1 H NMR (500 MHz, CD2Cl2) δ 7.48 – 7.43 (m,1H), 7.40 – 7.35 (m, 1H), 7.30 – 7.25 (m, 2H), 7.21 – 7.06 (m, 27H), 6.98 –6.93 (m, 1H), 6.62 – 6.59 (m, 1H), 4.89 (bs, 1H), 4.42 (bs, 1H), 4.15 (bs,1H), 3.99 (bs 1H), 2.52 (bs ​​3H), 2.04 (bs, 6H), 1.83 – 1.78 (m, 9H), 1.60 –1.57 (m, 12H), 1.42 – 1.40 (m, 3H); 31 P NMR (202 MHz) 58.3 ppm (bs).

[0096] Example 4. Synthesis of palladium precatalyst (Pd-1.7) (palladium ring G6 type).

[0097] AdQphos (1,182 mg, 0.21 mmol), bromoaryl (67 mg, 0.3 mmol), and palladium precursor (78.1 mg, 0.2 mmol) were placed in a 20 mL Schlenk flask containing a PTFE-coated stir bar. The container was sealed with a rubber diaphragm, evacuated, and purged with nitrogen. This cycle was repeated twice. Next, anhydrous THF (5 mL) was added, and the mixture was stirred for 16 hours. Subsequently, a sample of the reaction was taken. 31 P NMR analysis showed complete and significant consumption of AdQPhos. The solvent was removed and the resulting solid was washed with pentane to yield the final product Pd-1.7 (133 mg, 53%).

[0098] (AdQPhos)Pd G6(Pd-1.7): 1 H NMR (500 MHz, CD2Cl2) δ 7.42 – 7.07 (m,34H), 4.80 (d, J = 10 Hz, 2H), 4.61 (d, J = 5 Hz, 2H), 1.93 – 1.87 (m, 6H), 1.78 – 1.74 (m, 9H), 1.60 – 1.54 (m, 15H); 31 P NMR (202 MHz) 41.2 ppm (s).

[0099] Example 5. Synthesis of AdMPhos(4) and its precatalyst (Pd-4.1) 1-Bromoferrocene (4a, 1.0 g, 3.77 mmol) was placed in a 50 mL Schlenk flask containing a PTFE-coated stir bar. The container was sealed with a rubber diaphragm, evacuated, and purged with nitrogen. This cycle was repeated twice. Next, anhydrous THF (20 mL) was added, and the mixture was stirred for 5 minutes. The solution was cooled to -78°C, and then nBuLi (2.6 M, 2.9 mL, 7.72 mmol in hexane) was added in another flask over 15 minutes. The mixture was stirred for 2 hours, and a significant precipitation was observed (indicating lithiation). Subsequently, di(1-adamantyl)chlorophosphine (0.75 M, 8.0 mmol) in THF was added dropwise. The solution was allowed to warm to room temperature and stirred overnight (18 hours). After 18 hours, a large amount of precipitation was observed, and the reaction mixture was sampled. 31 P NMR analysis indicated a significant consumption of the starting material. The solution was cooled to 0–5°C in an ice bath. The pure product precipitated and was filtered under nitrogen. The resulting solid was washed with diethyl ether and pentane to give pure product 4 (yellow solid, 0.72 g, 62%).

[0100] AdMPhos (4, 100.0 mg, 0.13 mmol) and the palladium precursor (36.3 mg, 0.13 mmol) were placed in a 20 mL Schlenk flask with a PTFE-coated stir bar. The container was sealed with a rubber diaphragm, evacuated, and purged with nitrogen. This cycle was repeated twice. Next, anhydrous DCM (5 mL) was added, and the mixture was stirred for 5 hours. Subsequently, a sample of the reaction was taken. 31 P NMR analysis showed complete consumption of ligand 4. The solvent was removed and the resulting solid was washed with pentane to yield the final product Pd-4.1 (113 mg, 90%).

[0101] (AdMPhos)PdCl2(Pd-4.1): 1 H NMR (500 MHz, cd2cl2) δ 4.71 – 4.28 (m, 8H),2.44 – 1.44 (m, 60H); 31 P NMR (202 MHz) 59.6 ppm.

[0102] Application of palladium precatalysts in palladium-catalyzed organic conversion Example 6. Palladium-catalyzed sp 2 -sp 3 Coupling reaction Various precatalysts (1.0 mol%), 2-bromobiphenyl (0.17 mL, 1.0 mmol, 1.0 equivalent), and a stir bar were placed in 20 mL vials. The mixture was dissolved in THF (5 mL). Then, isopropyl-Nu solution (iPrZnBr: 4.0 mL, 0.5 M, 2.0 mmol, 2.0 equivalent) was added dropwise and the mixture was stirred at room temperature for 6 hours. The reaction yield was determined by GC. For the reaction with isopropyllithium, the Ferringa procedure was used. The individual reactions are shown in Table 1 below.

[0103] Table 1: Reactions in Example 6 entry Nucleophilic reagent [Nu] Precatalyst [Pd] <![CDATA[GC yield (%) (*) <!-- 19 -->]]> 1 Li <![CDATA[AdQPhos (1): Pd2(dba)3]]> 99 (32.3 : 1) 2 ZnBr <![CDATA[AdQPhos (1): Pd2(dba)3]]> 29.9 (3 : 1) 3 ZnBr <![CDATA[QPhos: Pd2(dba)3]]> Trace 4 ZnBr AdQPhosPd(crotonyl)Cl (Pd-1.2) 84 (2.9 : 1) 5 ZnBr AdQPhosPdG3 (Pd-1.4) 89 (3 : 1) 6 ZnBr <![CDATA[AdMPhosPdCl2(Pd-4.1)]]> 75 (4.2 : 1) (*)GC yield: The ratio refers to 2-isopropylbiphenyl: 2-(n-propyl)biphenyl.

[0104] 2-Isopropylbiphenyl: 1 H NMR (500 MHz, CDCl3) δ 7.48 – 7.43 (m, 3H), 7.41 (d, J =10 Hz, 2H), 7.36 – 7.33 (m, 2H), 7.28 – 7.22 (m, 2H), 3.18 – 3.15 (m, 1H), 1.21 (d, J = 10 Hz, 6H) ppm.

[0105] 2-Isopropylnaphthalene: 1 H NMR (500 MHz, CDCl3) δ 7.82 – 7.78 (m, 3H), 7.65 (s,1H), 7.5 – 7.39 (m, 3H), 3.08 – 3.15 (m, 1H), 1.35 (d, J = 10 Hz, 6H) ppm.

[0106] Example 7. Palladium-catalyzed CO coupling reaction Various pre-catalysts (1.0 mol%), 4-nitrobromobenzene (0.17 mL, 1.0 mmol, 1.0 equivalent), sodium tert-butoxide (60 mg, 0.62 mmol, 1.25 equivalent), and a stir bar were placed in 4 mL vials. The mixture was dissolved in toluene (2 mL). The mixture was then stirred at 50°C. The reaction yields were determined by GC. The individual reactions are shown in Table 2 below.

[0107] Table 2: Reactions in Example 7 entry Precatalyst [Pd] GC yield (%) 1 <![CDATA[AdQPhos (1) : Pd2(dba)3]]> 99% (separation yield 89%) 2 <![CDATA[(p - Tolyl)AdQPhos(2):Pd 2( dba)3]]> 90% 3 <![CDATA[( p -CF3-C6H4)AdQPhos (3) : Pd2(dba)3]]> 91% 4 <![CDATA[QPhos : Pd2(dba)3]]> 74%

[0108] 4-tert-butoxynitrobenzene: 1 H NMR (500 MHz, CDCl3) δ 8.16 (d, J = 10 Hz, 2H), 7.04(d, J = 5 Hz, 2H), 1.46 (s, 9H) ppm.

[0109] Example 8. Palladium-catalyzed CS coupling reaction Various precatalysts (2.0 mol%), 4-bromoanisole (0.063 mL, 0.5 mmol, 2.0 equivalent), sodium tert-butoxide (72 mg, 0.75 mmol, 3.0 equivalent), and a stir bar were placed in 4 mL vials. The mixture was dissolved in toluene (2 mL). Subsequently, hexamethylenetetramine (0.035 mL, 0.25 mmol, 1.0 equivalent) was added, and the mixture was stirred at 70°C. The reaction yields were determined by GC. The individual reactions are shown in Table 3 below.

[0110] Table 3: Reactions in Example 8 entry Precatalyst [Pd] GC yield (%) 1 <![CDATA[AdQPhos(1):Pd2(dba)3]]> 86% (separation yield 63%) 2 AdQPhosPd(crotonyl)Cl(Pd-1.2) 44 3 <![CDATA[AdMPhosPdCl2(Pd-4.1)]]> 60

[0111] 1-(hexathio)-4-methoxybenzene: 1 H NMR (500 MHz, CDCl3) δ 7.33 (d, J = 10 Hz, 2H), 6.84 (d, J = 10 Hz, 2H), 3.85 (s,3H), 2.81 (t, J = 10 Hz, 2H), 1.60 – 1.55 (m,2H), 1.46 – 1.55 (m, 2H), 1.30 – 1.26 (m, 4H), 0.88 (t, J = 10 Hz, 3H) ppm.

[0112] Example 9: Palladium-catalyzed α-arylation of ketones Various precatalysts (1.0 mol%), 4-fluorobromobenzene (0.26 mL, 2.0 mmol, 2.1 equivalents), ethyl phenyl ketone (0.14 mL, 1.0 mmol, 1.0 equivalents), sodium tert-butoxide (153 mg, 1.5 mmol, 1.5 equivalents), and a stir bar were placed in 20 mL vials. The mixture was dissolved in THF (5 mL). The mixture was then stirred at 50°C. The reaction yields were determined by GC. The individual reactions are shown in Table 4 below.

[0113] Table 4: Reactions in Example 9 entry Precatalyst [Pd] GC yield (%) 1 AdQPhosPd(crotonyl)Cl(Pd-1.2) 84 2 AdQPhosPdG3 (Pd-1.4) 75 3 <![CDATA[AdQPhos (1) : Pd2(dba)3]]> 99 4 <![CDATA[QPhos : Pd2(dba)3]]> 98 5 <![CDATA[AdMPhosPdCl2(Pd-4.1)]]> 89

[0114] product: 1 H NMR (500 MHz, CDCl3) δ 7.96 (d, J = 10 Hz, 2H), 7.42 (d, J = 10 Hz,2H), 7.29 – 7.26 (m, 2H), 7.02 – 6.99 (m, 2H), 4.71 (q, J = 10 Hz, 1H) 1.54 (d, J = 5 Hz, 3H) ppm.

[0115] Example 10: Palladium-catalyzed α-arylation of amides The amide (73.59 mg; 0.50 mmol; 1.00 equivalent), precatalyst (2 mol%), and stir bar were placed in a 20 mL vial. The mixture was dissolved in THF. Then, bromobenzene (0.06 mL; 0.55 mmol; 1.10 equivalent) was added and the mixture was stirred for 5 minutes. A solution of lithium bis(trimethylsilyl)amide was then added in portions to 1.0 M THF (0.55 mL; 0.55 mmol; 1.10 equivalent), and the mixture was stirred at 70°C for 20 hours. Conversion was measured using GC. The individual reactions are shown in Table 5 below.

[0116] Table 5: Reactions in Example 10 entry Precatalyst [Pd] GC yield (%) 1 <![CDATA[AdQPhos(1):Pd2(dba)3]]> 44 2 <![CDATA[(p - Tolyl)AdQPhos(2):Pd2(dba)3]]> 20 3 <![CDATA[QPhos:Pd2(dba)3]]> Trace 4 AdQPhosPd(crotonyl)Cl(Pd-1.2) 79 5 AdQPhosPdG3 (Pd-1.4) 83 (74% separation)

[0117] product: 1H NMR (500 MHz, CDCl3) δ 7.37 – 7.33 (m, 3H), 7.30 – 7.28 (m, 1H), 7.21 – 7.16 (m, 3H), 7.06 (t, J = 10 Hz, 1H), 6.90 (d, J = 10 Hz, 1H), 4.61(s, 1H), 3.26(s, 3H) ppm.

[0118] Example 11: Palladium-catalyzed α-arylation of nitroalkanes The precatalyst (2 mol%), nitropropane (0.45 mL; 5.0 mmol; 10 equivalents), 4-bromoanisole (0.06 mL, 0.5 mmol, 1.0 equivalents), K3PO4 (127.2 mg, 0.75 mmol, 1.5 equivalents), and a stir bar were placed in a 20 mL vial. This mixture was dissolved in 1,4-dioxane. The mixture was then stirred at 60°C for 20 hours. Conversion was measured using GC. The individual reactions are shown in Table 6 below.

[0119] Table 6: Reactions in Example 11 entry Precatalyst [Pd] GC yield (%) 1 <![CDATA[AdQPhos (1) : Pd2(dba)3]]> 39 2 <![CDATA[(p - Tolyl)AdQPhos(2):Pd 2( dba)3]]> 53 3 <![CDATA[QPhos : Pd2(dba)3]]> Trace 4 AdQPhosPd(crotonyl)Cl(Pd-1.2) 89 (80% separation) 5 AdQPhosPdG3 (Pd-1.4) 84

[0120] Example 12: Palladium-catalyzed α-arylation of nitrile The precatalyst (2 mol%), nitrile (0.07 mL; 0.5 mmol; 1.0 equivalent), 4-bromoanisole (0.06 mL, 0.5 mmol, 1.0 equivalent), K3PO4 (318 mg, 1.5 mmol, 3.0 equivalent), and a stir bar were placed in a 20 mL vial. This mixture was dissolved in 1,4-dioxane. The mixture was then stirred at 60°C for 20 hours. The conversion was determined using GC. The individual reactions are shown in Table 7 below.

[0121] Table 7: Reactions in Example 12 entry Precatalyst [Pd] GC yield (%) 1 <![CDATA[AdQPhos (1) : Pd2(dba)3]]> 11 2 <![CDATA[(p - Tolyl)AdQPhos (2): Pd2(dba)3]]> 27 3 <![CDATA[QPhos : Pd2(dba)3]]> Trace 4 AdQPhosPd(crotonyl)Cl (Pd-1.2) 73 5 AdQPhosPdG3 (Pd-1.4) 60

[0122] Example 13: Palladium-catalyzed α-arylation of esters The precatalyst (3 mol%), ester (200 mg, 1.22 mmol, 2.4 equivalents), and PTFE-coated stir bar were placed in a 20 mL vial. Anhydrous toluene was then added, and the mixture was stirred for 2 minutes. LiHMDS (1.25 mmol) was added to the solution at 0°C. The mixture was stirred for 10 minutes. Subsequently, a solution of 4-bromoanisole in 0.5 mL of toluene was added dropwise. The mixture was then stirred at 70°C for 20 hours. The conversion was measured using GC. The individual reactions are shown in Table 8 below.

[0123] Table 8: Reactions in Example 13 entry Precatalyst [Pd] GC yield (%) 1 <![CDATA[AdQPhos (1) : Pd2(dba)3]]> 89 2 <![CDATA[(p - Tolyl)AdQPhos (2): Pd2(dba)3]]> 64 3 <![CDATA[( p -CF3-C6H4)AdQPhos (3) : Pd2(dba)3]]> 50 4 <![CDATA[QPhos : Pd2(dba)3]]> Trace 5 AdQPhosPd(crotonyl)Cl (Pd-1.2) 99 6 AdQPhosPdG3 (Pd-1.4) 60 7 <![CDATA[AdMPhosPdCl2(Pd-4.1)]]> 73

[0124] Example 14: Palladium-catalyzed PC coupling reaction Various pre-catalysts (5.0 mol%), 4-bromoanisole (0.032 mL, 0.25 mmol, 1.0 equivalent), sodium tert-butoxide (72 mg, 0.75 mmol, 3.0 equivalent), and a stir bar were placed in a 4 mL vial. The mixture was dissolved in toluene (2 mL). Then, Ad2PH (83 mg, 0.25 mmol, 1.1 equivalent) was added, and the mixture was stirred at 70°C. The reaction yield was determined by... 31 PNMR determination. The reactions are shown in Table 9 below.

[0125] Table 9: Reactions in Example 14 entry Precatalyst [Pd] Product yield (%) 1 <![CDATA[AdQPhos (1) : Pd2(dba)3]]> 88.5 2 AdQPhosPd(crotonyl)Cl (Pd-1.2) 92.5 3 <![CDATA[AdMPhosPdCl2(Pd-4.1)]]> 33 4 <![CDATA[QPhos : Pd2(dba)3]]> 80

[0126] The embodiments provided herein are in no way intended to limit the scope of the invention as set forth in the claims.

[0127] References (1) (a) DS Surry, SL Buchwald, Chem. Sci. 2011, 2 , 27–50; (b) CCCJohansson Seechurn, MO Kitching, TJ Colacot, V. Snieckus, Angew. Chem. Int. Ed. 2012, 51 , 5062–5085. (2) (a) GA Grasa, TJ Colacot, Org. Lett. 2007, 9 , 5489–5492; (b)RCJ Atkinson, NJ Long, Monodentate Ferrocene Donor Ligands , in P.Stepnicka, Ferrocenes: Ligands, Materials and Biomolecules , Wiley, 2008; (c)TJ Colacot, Chem. Rev. 2003, 103 , 3101–3118. (3) GP Sollott, HE Mertwoy, S. Portnoy, JL Snead, J. Org. Chem. 1963, 28 , 1090–1092. (4) GR Knox, PL Pauson, D. Willison, Organometallics 1992, 11 , 2930–2933. (5) S. Juge, JP Genet, Tetrahedron Lett. 1989, 30 , 2783–2786. (6) EA Colby, TF Jamison, J. Org. Chem. 2003, 68 , 156–166. (7) N. Kataoka, Q. Shelby, JP Stambuli, JF Hartwig, J. Org. Chem. 2002, 67 , 5553–5566. (8) (a) NA Strotman, HR Chobanian, J. He, Y. Guo, PG Dormer,CM Jones, JE Steves, J. Org. Chem. 2010, 75 , 1733–1739; (b) D. Cheng, J.Liu, D. Han, G. Zhang, W. Gao, MH Hsieh, N. Ng, S. Kasibhatla, C. Tompkins,J. Li, et al., ACS Med. Chem. Lett. 2016, 7, 676–680; (c) Y. Ohtake, T. Sato, T.Kobayashi, M. Nishimoto, N. Taka, K. Takano, K. Yamamoto, M. Ohmori, M.Yamaguchi, K. Takami, et al., J. Med. Chem. 2012, 55 , 7828–7840. (9) C.C.C. Johansson Seechurn, S.L. Parisel, T.J. Colacot, J. Org. Chem. 2011, 76 , 7918–7932.

Claims

1. A compound of formula I: in: Cp 1 Represented by Equation II or Equation III R 1 Each occurrence is independently selected from arbitrarily substituted C6-C. 10 Aryl or C3-C9 heteroaryl; Ad is an adamantyl alkyl group; and When present, each optional substituent is selected from C1-C4 alkyl, C1-C4 haloalkyl, and C1-C4 alkoxy groups.

2. The compound according to claim 1, wherein the compound is represented by formula IV. Where R 1 And Ad as defined in claim 1.

3. The compound according to claim 1 or 2, wherein R 1 Each of the optional substituents is selected independently from the other of the substituted C6 aryl groups when it appears; and each optional substituent is selected from C1-C4 alkyl, C1-C4 haloalkyl and C1-C4 alkoxy groups when present.

4. The compound according to claim 1, wherein the compound is represented by formula V: Where Ad is as defined in claim 1.

5. The compound according to claim 1, wherein the compound is selected from... 。 6. A method for synthesizing the compound according to claim 2, comprising the following steps: (a) Lithate the compound according to formula A and react it with Ad2PY 2 The reaction is carried out to obtain a compound according to formula B; as well as (b) In the presence of a base and a catalytic amount of Pd(OAc)2, the compound according to formula B is reacted with R. 1 Y 3 The reaction is carried out to obtain the compound according to formula IV; in: Y 1 Selected from halogen atoms or hydrogen atoms; Y 2 Y 3 They are selected independently from halogen atoms; R 1 Each occurrence is independently selected from arbitrarily substituted C6-C. 10 Aryl or C3-C9 heteroaryl; Ad is an adamantyl alkyl group; and When present, each optional substituent is selected from C1-C4 alkyl, C1-C4 haloalkyl, and C1-C4 alkoxy groups.

7. The method according to claim 6, wherein the lithiation in step (a) is carried out by reacting the compound according to formula A with an organolithium reagent.

8. The method according to claim 6 or 7, wherein the base in step (b) is an alkali metal alkoxide or an alkaline earth metal alkoxide.

9. A method for synthesizing the compound according to claim 4, comprising the following steps: (a') Lithate the compound according to formula C and react it with Ad2PY 2 The reaction is carried out to give the compound according to formula V: in: Y 1 Selected from halogen atoms or hydrogen atoms; Y 2 Selected from halogen atoms; and Ad stands for adamantyl alkyl group.

10. The method according to claim 9, wherein the lithiation in step (a') is carried out by reacting the compound according to formula C with an organolithium reagent.

11. Precatalysts of Formula VI or Formula VII: in: R 1 Each occurrence is independently selected from arbitrarily substituted C6-C. 10 Aryl or C3-C9 heteroaryl; Ad is an adamantyl alkyl group; M is a transition metal selected from Group 9, Group 10 or Group 11; X is selected from halogens, trifluoromethanesulfonate (TfO) – ), tetrafluoroborate (BF4) – ), hexafluorophosphate (PF6) – ), mesylate (MsO) – ), Toluenesulfonate (TsO) – ), tetrakis[3,5-bis(trifluoromethyl)phenyl]borate (B[(CF3)2C6H3]4 – ), hexafluoroantimonate (SbF6) – ) and their combinations; Ar represents the substituted C6-C. 10 Aryl; and When present, each optional substituent is selected from C1-C4 alkyl, C1-C4 haloalkyl, and C1-C4 alkoxy groups.

12. The precatalyst according to claim 11, wherein R 1 Each of the optional substituents is selected independently from the other of the substituted C6 aryl groups when it appears; and each optional substituent is selected from C1-C4 alkyl, C1-C4 haloalkyl and C1-C4 alkoxy groups when present.

13. The precatalyst according to claim 11 or 12, wherein M is selected from Co, Rh, Ir, Ni, Pd, Pt, Cu, Ag and Au, preferably Ni, Pd and Pt, and more preferably M is Pd.

14. The precatalyst according to one or more of claims 11 to 13, wherein Ar is optionally a substituted C6 aryl group.

15. The precatalyst according to one or more of claims 11 to 14, wherein the precatalyst is selected from... in: Ad is 1-adamantyl; Ar is Ph or p-(trifluoromethyl)phenyl; and X is selected from chloride ions (Cl... – ), bromide ions (Br) – ), trifluoromethanesulfonate (TfO) – ) and mesylate (MsO) – ).

16. Precatalysts of Formula VIII or Formula IX: in: R 1 Each occurrence is independently selected from arbitrarily substituted C6-C. 10 Aryl or C3-C9 heteroaryl; Ad is an adamantyl alkyl group; M is a transition metal selected from Group 9, Group 10 or Group 11; X is selected from halogens, trifluoromethanesulfonate (TfO) – ), tetrafluoroborate (BF4) – ), hexafluorophosphate (PF6) – ), mesylate (MsO) – ), Toluenesulfonate (TsO) – ), tetrakis[3,5-bis(trifluoromethyl)phenyl]borate (B[(CF3)2C6H3]4 – ), hexafluoroantimonate (SbF6) – ) and their combinations; R 2 Selected from H, C1-C4 alkyl and C6-C 10 Aryl; and When present, each optional substituent is selected from C1-C4 alkyl, C1-C4 haloalkyl, and C1-C4 alkoxy groups.

17. The precatalyst according to claim 16, wherein R 1 Each of the optional substituents is selected independently from the other of the substituted C6 aryl groups when it appears; and each optional substituent is selected from C1-C4 alkyl, C1-C4 haloalkyl and C1-C4 alkoxy groups when it is present.

18. The precatalyst according to claim 16 or 17, wherein M is selected from Co, Rh, Ir, Ni, Pd, Pt, Cu, Ag and Au, preferably Ni, Pd and Pt, and more preferably M is Pd.

19. The precatalyst according to one or more of claims 16 to 18, wherein the precatalyst is selected from... in: Ad is 1-adamantyl; R 2 Selected from H, Me, and Ph; and X is selected from chloride ions (Cl... – ), bromide ions (Br) – ), iodide ions (I) – ), trifluoromethanesulfonate (TfO) – ), tetrafluoroborate (BF4) – ) and hexafluorophosphate (PF6) – ).

20. Precatalysts of formula X or XI: in: R 1 Each occurrence is independently selected from arbitrarily substituted C6-C. 10 Aryl or C3-C9 heteroaryl; Ad is an adamantyl alkyl group; M is a transition metal selected from Group 9, Group 10 or Group 11; X is selected from halogens, trifluoromethanesulfonate (TfO) – ), tetrafluoroborate (BF4) – ), hexafluorophosphate (PF6) – ), mesylate (MsO) – ), Toluenesulfonate (TsO) – ), tetrakis[3,5-bis(trifluoromethyl)phenyl]borate (B[(CF3)2C6H3]4 – ), hexafluoroantimonate (SbF6) – ) and their combinations; R 3 Selected from H, Me, NHMe, Ph, and NHPh; and When present, each optional substituent is selected from C1-C4 alkyl, C1-C4 haloalkyl, and C1-C4 alkoxy groups.

21. The precatalyst according to claim 20, wherein R 1 Each of the optional substituents is selected independently from the other of the substituted C6 aryl groups when it appears; and each optional substituent is selected from C1-C4 alkyl, C1-C4 haloalkyl and C1-C4 alkoxy groups when it is present.

22. The precatalyst according to claim 20 or 21, wherein M is selected from Co, Rh, Ir, Ni, Pd, Pt, Cu, Ag and Au, preferably Ni, Pd and Pt, and more preferably M is Pd.

23. The precatalyst according to one or more of claims 20 to 22, wherein the precatalyst is selected from... in: Ad is 1-adamantyl; and X is the mesylate ion (MsO) – ).

24. A method for carrying out a transition metal-catalyzed coupling reaction between a first substrate and a second substrate, wherein the method comprises the following steps: (a) Providing in a reaction vessel (i) the compound and transition metal source according to one or more of claims 1 to 5, or (ii) the precatalyst according to one or more of claims 11 to 23; (b) Add the first and second substrates to the reaction vessel; as well as (c) React the first and second substrates at a temperature and time sufficient for transition metal catalytic coupling reactions.

25. The method of claim 24, wherein the transition metal source is a Pd metal source and the precatalyst is a Pd precatalyst.

26. The method according to claim 24 or 25, wherein the transition metal catalytic coupling reaction is selected from C(sp...) 2 )-C(sp 2 Coupling reaction, C(sp) 2 )-C(sp 3 Coupling reaction, C(sp) 2 )-N coupling reaction, C(sp 2 )-O coupling reaction, C(sp 2 )-S coupling reaction, C(sp 2 )-P coupling reaction or α-arylation of amides, esters, nitriles, nitroalkanes or ketones.

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